In Part I we
reviewed the basic advantages of effective perioperative, multimodal pain
control. Analgesics coupled with sedative/tranquilizers provide a more
comfortable patient experience, reduce induction and maintenance agent
requirements, and generally improve patient morbidity and mortality.
Multimodal techniques reduce the dose of each individual drug which, in
turn, reduces the potential for adverse drug effects. The pain pathway is
a tinderbox. Once in flames, it is difficult to put out. Intervening
before the pain system becomes sensitized is an absolute necessity when
your goal is optimal patient benefit.

Perioperative pain management planning is most
effective, and the outcome is more attractive, when each patient is looked
upon as an individual. No single protocol, no single drug dose, could
possibly be consistently safe and effective across the broad spectrum that
comprises the veterinary patient pool. Advanced anesthesia and pain
management is partially an art, not simply a mathematical exercise.
Patient variables suggesting that higher drug doses should be considered
include younger age, smaller size, excitable nature, and good health.
Patient variables suggesting that lower doses be considered or that one
should forego a drug family altogether include older age, larger size,
calm nature, and poor health. In Part II, current information about the
various drug families and individual agents will be discussed.

OPIOIDS remain the most important perioperative drug family. Opioids form the
basis upon which perioperative strategies should be based. With few
exceptions, these drugs are well tolerated. Their negative effects are
easily controlled. They can be delivered by many different routes
including intramuscular, transmucosal, IV bolus, IV CRI (constant rate
infusion), and orally in some instances. These drugs can provide both
sedation and pain relief but these qualities vary significantly between
opioids. Significant side effects are not common at appropriate doses. It
is critical that the anesthesiologist understand the basic advantages and
shortcomings of the more common opioids in order to gain their best
overall benefit.

BUTORPHANOL

BUTORPHANOL is a kappa agonist with
moderate sedative effects capable of providing mild analgesia. Often the
sedation outlasts the analgesia. Canine studies have failed to demonstrate
analgesia past 45 minutes[i],[ii].
Feline studies have failed to show analgesia past 90 minutes[iii],,[iv].
In fact some studies have failed to show analgesia of any significance in
dogs and cats[v],[vi].
Interestingly, Lascelles & Robertson’s research in cats failed to
demonstrate a difference in the analgesic intensity or duration as the
dose was increased from 0.1 mg/kg to 0.8 mg/kg4. A significant
number of these healthy cats demonstrated dysphoria when butorphanol was
used as a sole agent.

Butorphanol 0.2 to 0.4 mg/kg can be combined
with either acepromazine or medetomidine in healthy patients to create an
effective preanesthetic or procedural sedation combination. Butorphanol
can also be combined with a benzodiazepine, either midazolam or diazepam,
to sedate aged and less healthy patients. Butorphanol is not an
effective analgesic when delivered by the oral route as butorphanol
undergoes significant first-pass metabolism after oral administration.
Couple the low oral bioavailability with butorphanol’s short duration of
effect and you would have to give a dog at least 1.0 mg/kg every 45
minutes to gain any meaningful analgesia.

A logical companion for butorphanol is
buprenorphine. Butorphanol’s analgesic onset is rapid but the mild
analgesia is of short duration. Buprenorphine’s time to peak analgesic
effect is quite slow even when given by the IV route but its analgesic
duration can be quite long. When administered together, butorphanol’s
short-term analgesia wanes as buprenorphine is reaching its peak effect.

One additional application for butorphanol is
that of a mu antagonist. If a patient is exhibiting undesirable mu agonist
effects while on morphine or hydromorphone (dysphoria, excess sedation, or
excessive respiratory depression) butorphanol can reduce the unwanted mu
agonist effects without total loss of patient analgesia.

In general, butorphanol does NOT give you much
bang for the buck. Butorphanol costs about ten times more than morphine,
per dose, while providing much more limited analgesia of much shorter
duration.

NALBUPHINE

NALBUPHINE possesses similar qualities
to butorphanol and can be used in similar situations. The sedative effects
are minimal when used alone but it is an effective component for
procedural sedation or for initial preanesthetic sedation and analgesia;
the sedation is somewhat less intense than, and the duration of effect 10
to 15 minutes less than, that of butorphanol containing combinations. Like
butorphanol, nalbuphine provides mild analgesia of short duration.
Nalbuphine can be dosed similar to butorphanol at 0.2 to 0.4 mg/kg up to
1.0 mg/kg in combination with acepromazine, medetomidine, or midazolam.
See www.vasg.org/13_week_old_m.htm for videos demonstrating the differences between nalbuphine/medetomidine
and butorphanol/medetomidine combinations in cats.

Like butorphanol, nalbuphine can be used to
antagonize unwanted mu agonist effects without total loss of patient
analgesia. Unlike butorphanol, nalbuphine is not a scheduled drug reducing
the paper trail burden of the practice. At 1/6th to 1/12th the cost of butorphanol, nalbuphine warrants inclusion in the drug
inventory. See www.vasg.org/drugs_sources_and_costs.htm for drug costs and supplier information.

BUPRENORPHINE

BUPRENORPHINE is a considerably more
capable analgesic. While it is usually classified as a partial mu agonist,
detailed research reveals complex interactions at the mu, delta, kappa,
and ORL-1 receptors[vii],[viii],[ix].
Buprenorphine is capable of providing analgesia for mild to moderate pain
and, as newer animal research suggests, may be capable of handling more
severe pain at higher doses than are currently being recommended8.
There is considerable debate about the effect of dose on the analgesic
intensity and the duration of effect.

In general, higher doses are expected to
provide a longer duration of effect. Sheilah Robertson’s work at the
University of Florida supports that premise but no one has yet clearly
defined the exact relationship between dose and duration. Table 1 below
sums up a reasonable dose range including approximate durations of
analgesic effect.

Increasing buprenorphine’s dose increases the
analgesic intensity but only to a point. Buprenorphine’s dose/effect
analgesia can be characterized as a bell shaped curve with higher doses,
at a variable point depending on the pain model studied, exerting a
diminution of the analgesic intensity8. It appears that the
dose at which you may see a reduction in analgesia is at or well above 0.1
mg/kg8,[x], [xi].

Buprenorphine is remarkably free of adverse
effects. Sedation, vomiting, and respiratory depression are rarely seen
with buprenorphine. This lack of consistent sedation makes the drug
unattractive as a solo opioid in a preanesthetic medication strategy for
healthy patients.

Buprenorphine has a delayed onset, even when
given IV, that needs to be taken into account for best effect. Given
IV, peak effect occurs in about 30 minutes. Given IM, peak effect occurs
in 45 to 60 minutes[xii].
Data from Dr. Robertson’s feline hydromorphone studies have shown SQ
administration to be the least effective route, even in healthy cats[xiii].
Therefore, subcutaneous administration is not recommended.

Transmucosal (TM) absorption has been shown
to be an effective route of administration in cats[xiv].
It appears to be as effective as IV administration. The alkaline pH of the
cat’s oral cavity favors the un-ionized form of the drug enhancing the
drug’s absorption. Placing the drug inside the cheek pouch or
sublingually is easier than conventional oral drug administration. Coupled
with the potential for long-term analgesia at proper dose, TM
buprenorphine is an extremely attractive home analgesic medication for
cats. Transmucosal administration should not be confused with oral (PO)
delivery. Buprenorphine is not effective when combined with a liquidand administered orally. The enterohepatic first-pass effect
removes 90+% of the drug before it can reach systemic circulation
rendering that route impractical[xv].

To date, no canine oral mucosal absorption
studies have been performed leaving the details of that question
unanswered. Oral mucosal absorption undoubtedly does occur in dogs but the
bioavailabilty percentage is not yet known. We know that the transmucosal
bioavailability in humans is 30% to 50% (possibly as high as 75%)[xvi].
Human pH is neutral to slightly acidic while canine saliva is slightly
alkaline. It is likely that TM buprenorphine bioavailability in dogs is
similar, if not superior, to that in humans. Adjusting the drug dose to
compensate for the reduced bioavailability makes TM buprenorphine
theoretically useful in dogs but expensive.

Combining buprenorphine with other opioids
presents a variety of debatable consequences. Combining buprenorphine
with a kappa agonist like butorphanol or nalbuphine might seem
counterintuitive but it is a combination that the author supports for
procedures producing mild to moderate pain. Buprenorphine is primarily a
partial mu agonist with the available studies supporting opposing opinions
about kappa receptor agonism/antagonism depending on the species and the
study; more recent studies support an agonistic kappa effect in animals[xvii],[xviii].
Butorphanol is a kappa agonist with mu antagonistic properties. When the
two drugs are given together, butorphanol provides an immediate sedative
and analgesic benefit, but one of short duration. Butorphanol’s
analgesia wanes about the same time that buprenorphine reaches its peak
analgesic effect. Combining buprenorphine with a mu agonist might also
seem to present a conflict, possibly reducing the mu agonist’s analgesic
benefit (partial agonists are generally regarded as less efficacious
analgesics than mu agonists with potential to antagonize mu agonist
effects). Fortunately, mu agonists form an additive, if not synergistic,
analgesic benefit for patients previously treated with therapeutic doses
of buprenorphine9,[xix].

Buprenorphine is also an attractive epidural
agent as it is preservative-free and it has compared favorably to
preservative free (PF) morphine in canine trials[xx].
One additional buprenorphine benefit is gained when buprenorphine is added
to local anesthetic blocks. Human studies have shown that 0.003 mg/kg
buprenorphine added to lidocaine and bupivacaine local blocks will
effectively double the duration of analgesic benefit[xxi].
Buprenorphine’s shortcoming is its cost.

THE MU AGONISTS include morphine,
hydromorphone, oxymorphone, methadone, and fentanyl. Inconsistent
availability and higher cost has made it more difficult to maintain
oxymorphone in the analgesic inventory. Methadone is significantly more
expensive in the United States than other areas of the world making its
use unattractive. Morphine, hydromorphone, and fentanyl serve as the core
opioids in most advanced practices. Of the mu agonists, morphine and
hydromorphone are the most attractive cost-effective analgesics.

Mu agonists have no ceiling effect. Higher
doses produce stronger effects, wanted and unwanted. Adverse effects
include vomiting, defecation, respiratory depression, dysphoria, and
bradycardia. There are significant differences between opioid induced
human concerns and veterinary concerns. Vomiting may persist with ongoing
mu agonist use in people but it is usually limited to a single episode in
dogs and cats. Transient nausea is a small penalty for superior analgesia.
Often a full stomach is emptied or a foreign body revealed that could have
been tomorrow’s GI obstruction. To be fair, vomiting should be avoided
if an upper GI obstruction is suspected, an esophageal foreign body is
present, or increased intracranial pressure is a concern. Defecation
provides a ready sample for parasitic evaluation.

Respiratory depression is a considerable
concern in human medicine but is rarely of great clinical concern in
veterinary patients (the exception being higher doses of fentanyl).
Dysphoria can usually be managed by including low doses of acepromazine,
medetomidine, or a benzodiazepine. Dysphoria may also be managed by the
administration of buprenorphine, nalbuphine, or butorphanol, reducing
dysphoric effect without losing all analgesic benefit. Bradycardia is the
easiest of all to manage. IF the bradycardia produces
clinically significant effects (i.e. a concerning drop in patient blood
pressure), anticholinergics should easily rectify the situation.

A reduction in opioid dosing is not
necessarily the best way to address concerns about opioid adverse effects.
For instance, Sheilah Robertson’s work has shown that hydromorphone
doses below 0.1 mg/kg fail to generate consistent analgesia of adequate
duration in cats. Paradoxically, opioid-induced hyperalgesia can occur at
very low opioid doses[xxii].

There are some exciting future possibilities
for opioid applications. One area of particular promise involves the
combination of ultra-low dose antagonists like naltrexone with mu agonists
and monoamine reuptake inhibitors. The net effect is enhanced analgesia
while reducing the potential for opioid tolerance and dependency[xxiii],[xxiv],[xxv].

MORPHINE

MORPHINE remains one of the most
attractive opioid agents. It is the most cost-effective and versatile mu
agonist. Morphine may be administered by intermittent injection, included
in constant rate infusions (CRIs), added to local blocks for extended
analgesic duration21, and included in epidural injections.

Morphine mania is a dated reference to research
conducted on cats at extreme doses far above those used clinically in cats
today. At appropriate doses, morphine is a very useful feline analgesic.
The cat’s uniquely limited glucuronyl transferase capability reduces the total morphine related
benefit as the active morphine metabolite, morphine-6-glucuronide,
is produced in lower quantity. The IV administration of morphine also
carries a caution. Rapid IV infusions can trigger histamine release
resulting in a transient negative effect on blood pressure. This is rarely
of great clinical concern, but can generally be avoided all together by
slowing the rate of administration.

Applications
for morphine include:

·Intermittent injections as a preanesthetic medication or for
ongoing pain management

oCats 0.1 to 0.5 mg/kg

oDogs 0.5 to 1.0 mg/kg

·CRI delivery at rates of 0.12 to 0.36 mg/kg/hr

oCommonly given with lidocaine and ketamine for a multimodal
infusion in cats and dogs helping to avoid the peaks and valleys
associated with intermittent injections

·The inclusion of 0.075 mg/kg morphine with bupivacaine
effectively doubles the duration of analgesia from local blocks including
intra-articular blocks21

Morphine is one of the more attractive opioids
when significant canine liver dysfunction exists. It is protein bound to a
lesser extent than most opioids preserving a more predictable dose-effect
relationship. Also, its route of metabolism in canines, glucuronidation,
is usually well preserved in liver disease.

HYDROMORPHONE

HYDROMORPHONE vies with morphine for
cost-effectiveness and versatility. It may also be administered by
intermittent injection, included in constant rate infusions (CRIs), added
to local blocks for extended analgesic duration, and included in epidural
injections. Unlike morphine, hydromorphone is not associated with
histamine release.

Hydromorphone is a more effective analgesic
than morphine for feline patients. Robertson’s work has shown that the
most ideal dose for cats is 0.1 mg/kg. That dose provides excellent
analgesia but you will see a transient hyperthermia in a significant
number of these feline patients. Temperatures may reach 1030 F
to 1060 F degrees, last a few hours, then self-resolves. The
usual timeframe is 2 to 6 hours post administration.

Dogs are dosed from 0.1 to 0.2 mg/kg. Vomiting,
as a one-time event at initial administration, is not uncommon. As with
oxymorphone, dogs often pant on hydromorphone making hydromorphone less
attractive when sedating patients for chest radiographs.

Applications
for hydromorphone include:

·Intermittent injections as a preanesthetic medication or for
ongoing pain management.

oCats 0.1 mg/kg.

oDogs 0.1 to 0.2 mg/kg.

·CRI delivery at rates of 0.025 to 0.075 mg/kg/hr.

oCommonly given with lidocaine and ketamine for a multimodal
infusion in cats and dogs helping to avoid the peaks and valleys
associated with intermittent injections.

·The inclusion of 0.015 mg/kg hydromorphone with bupivacaine
effectively doubles the duration of analgesia from local blocks including
intra-articular blocks.

·Hydromorphone is also an attractive epidural opioid at 0.04
to 0.1 mg/kg with saline q.s. to a total volume of 0.1 to 0.2 ml/kg.

FENTANYL

FENTANYL use is greatly influenced by
its short duration of effect. The short durations makes it generally less
attractive as a preanesthetic medication or for intermittent bolus
administration on an ongoing basis. Fentanyl is also unattractive as an
epidural agent; it is absorbed into systemic circulation almost as fast as
if administered by the IM route. The short duration of effect becomes an
advantage when the drug is administered by constant rate infusion making
the CRI more responsive. It is also well suited to intraoperative IV bolus
administration at key painful points in the procedure. Fentanyl, at high
dose rates, can be combined with midazolam to provide total intravenous
anesthesia (TIVA). This is a challenging form of anesthesia best reserved
for the advanced setting.

Fentanyl has more potential to cause
respiratory depression than the other mu agonists. At higher doses patient
ETCO2 monitoring becomes a critical element as pulse oximeter readings may
remain in the high 90s while the ETCO2 may be well above 100 mmHg. This is
not normally a concern at standard analgesic CRI dose rates.

The fentanyl patch has become popular due to
the allure of constant analgesia and ease of administration. While they
are nice additions to the analgesic pharmacy, their ability to supply
adequate analgesia is limited by many factors. There is an inherent
variability in the fentanyl absorption from patient to patient and even
from patch to patch in the same patient. The hypothermia associated with
an anesthetic procedure can drop the fentanyl absorption to zero[xxvi] while lying with the patch on a supplemental heat source may increase
blood plasma levels. It is important to note that, in studies, the 100 mcg
patch provided no better analgesia than the 50 mcg patch; two 50 mcg
patches, rather than one 100 mcg patch, are recommended for larger canine
patients[xxviii]. One additional caution; cats may experience
hyperthermia and dysphoria while on the patch which may force its removal.

Applications
for fentanyl include:

·Intermittent injections at 0.002 to 0.005 mg/kg for painful
points during a surgery to gain better patient control especially for
patients poorly tolerant of higher inhalant levels.

·CRI delivery at rates of 0.0012 to 0.0048 mg/kg/hr.

oCommonly given with lidocaine and ketamine for a multimodal
infusion in cats and dogs helping to avoid the peaks and valleys
associated with intermittent injections.

·Fentanyl patch placed long enough ahead of surgery to aid in
patient analgesia

[xix]Taylor
PM, Walsh CM. Does
buprenorphine premedication affect the action of fentanyl during
surgery in dogs? Proceedings of the Association of Veterinary Anaesthetists Spring
Meeting, Dublin, May 2002.